Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F22%3A00558978" target="_blank" >RIV/67985823:_____/22:00558978 - isvavai.cz</a>

Alternative codes found

RIV/61388963:_____/22:00558978 RIV/00216208:11120/22:43923229

Result on the web

<a href="https://doi.org/10.1111/bph.15841" target="_blank" >https://doi.org/10.1111/bph.15841</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/bph.15841" target="_blank" >10.1111/bph.15841</a>

Result language

angličtina

Original language name

Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations

Original language description

Background and Purpose N-methyl-D-aspartate receptors (NMDARs) play a critical role in synaptic plasticity, and mutations in human genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. Compounds with a positive allosteric effect are thought to compensate for reduced receptor function. Experimental Approach We have used whole-cell patch-clamp electrophysiology on recombinant rat NMDARs and human variants found in individuals with neuropsychiatric disorders, in combination with in silico modelling, to explore the site of action of novel epipregnanolone-based NMDAR modulators. Key Results Analysis of the action of 4-(20-oxo-5 beta-pregnan-3 beta-yl) butanoic acid (EPA-But) at the NMDAR indicates that the effect of this steroid with a “bent” structure is different from that of cholesterol and oxysterols and shares a disuse-dependent mechanism of NMDAR potentiation with the “planar” steroid 20-oxo-pregn-5-en-3 beta-yl sulfate (PE-S). The potentiating effects of EPA-But and PE-S are additive. Alanine scan mutagenesis identified residues that reduce the potentiating effect of EPA-But. No correlation was found between the effects of EPA-But and PE-S at mutated receptors that were less sensitive to either steroid. The relative degree of potentiation induced by the two steroids also differed in human NMDARs carrying rare variants of hGluN1 or hGluN2B subunits found in individuals with neuropsychiatric disorders, including intellectual disability, epilepsy, developmental delay, and autism spectrum disorder. Conclusion and Implications Our results show novel sites of action for pregnanolones at the NMDAR and provide an opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with glutamatergic system hypofunction.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

British Journal of Pharmacology

ISSN

0007-1188

e-ISSN

1476-5381

Volume of the periodical

179

Issue of the periodical within the volume

15

Country of publishing house

GB - UNITED KINGDOM

Number of pages

21

Pages from-to

3970-3990

UT code for WoS article

000779296100001

EID of the result in the Scopus database

2-s2.0-85127541114